ABSTRACT Epithelial barrier dysfunction has been implicated as central to initiation and propagation of allergic disease. Despite differences in location and histology, the epithelium of the skin, airway, and intestine commonly functions as a critical barrier against the environment, providing innate defense against pathogens and bridging innate and adaptive immune responses. Atopic march, high co-morbidities among allergic diseases, unity of mucosal responses in upper and lower airway allergic disease, and barrier defects in intact non-lesional skin of atopic dermatitis patients all point to a systemic aspect of allergy. However, systemic mechanisms that would drive common epithelial dysfunction in seemingly disparate allergic diseases remain elusive and are not well understood. By conducting comparative bioinformatics analysis of epithelial barriers in different diseases, we made striking preliminary observations about unexpected hormonal imbalances associated with epithelial dysfunction in allergy. In concordance with these findings, we detected significant changes in circulating levels of hormones in pediatric patients with asthma and eczema when compared to healthy controls, including a decrease in plasma levels of insulin and an increase in levels of triiodothyronine (T3) and growth hormone (GH). Strikingly, we found that hormone levels were equally altered in the plasma of food allergy patients avoiding trigger foods and not experiencing allergic inflammation, suggesting that hormonal changes may represent an overlooked but significant underlying component of allergic disease at the systemic level. Based on our preliminary findings, we formulated our central hypothesis that systemic changes in hormone levels promote regional dysfunction and remodeling of epithelial barriers in allergic disease. We propose to test this hypothesis with the following three specific aims: 1) to identify hormone-responsive genes and signaling networks in multiple allergic diseases, consistent with the concept of systemic pathogenesis, using a computational approach; 2) to determine whether systemic levels of hormones in allergic individuals are altered and correlate with tissue expression of hormone-responsive genes; and 3) to test whether hormonal imbalance promotes epithelial barrier dysfunction in absence of active inflammatory process, in organotypic epithelial cultures. Collectively, this study will investigate the connection between hormonal changes and epithelial dysfunction in asthma, atopic dermatitis, and food allergy, which represents an entirely overlooked systemic aspect of these diseases that has potential to be transformative to the field of allergy.